Throughout the world, currently lung cancer is a malignant tumor with highest incidence and mortality. Lung cancer can be divided into two main types: small cell lung cancer and non-small cell lung cancer, where the non-small cell lung cancer accounts for 80% of the total amount of the lung cancer patients. The conventional chemotherapy and radiation therapy against non-small cell lung cancer lack specificity. Through these treatments, certain therapeutic effect is achieved and the lifespan of the patients is prolonged in some degree, however these treatments also bring about many side effects. Therefore targeted therapies, which can avoid excessive damage to normal cells, are more and more appreciated by the academia in the field of tumor and a wide range of patients. In the targeted therapies, epidermal growth factor receptor (EGFR) inhibitors play a significant role.
EGFR, a tyrosine kinase receptor, is a member of HER/ErbB family. The HER/ErbB family includes EGFR, HER2, HER3 and HER4, which are consist of three parts: an extracellular ligand-binding domain, a transmembrane domain consists of single chain, and a intracellular tyrosine kinase domain. EGFRs are widely distributed at the cell surface of the mammalian epithelial cells, fibroblasts, glial cells, keratinocytes, etc. The EGFR signaling pathway plays an important role in the physiological processes like cell growth, proliferation and differentiation, etc. The functional deficiency of protein tyrosine kinase like EGFR, or the abnormality in the activity or cellular localization of the key factors in the related signaling pathways, may all lead to occurrence of tumor, diabetes, immune deficiency and cardiovascular diseases.
So far the drugs related to EGFR available in the market includes: Gefitinib (Iressa®), Erlotinib (Tarceva®), which are selective EGFR tyrosine kinase inhibitors (EGFR-TKI); and Lapatinib (Tykerb®), which is an EGFR/HER2 dual inhibitor. They competitively bind the phosphorylation site of the tyrosine kinase at the intracellular segment to block the interaction between the phosphorylation site and ATP, and inhibit the phosphorylation of tyrosine and a series of downstream signal transduction, and then inhibit the growth of tumor cells. Among these drugs, the reversible EFGR inhibitor Gefitinib and Erlotinib show favorable therapeutic effects on non-small cell lung cancer patients with EGFR mutation; they can significantly prolong the progression-free survival (PFS) and overall survival (OS) of the patients. However, recent clinical use indicates that the PFS of most patients who are positive in EGFR mutation is no longer than 12˜14 months, and soon afterwards develop resistance to the EGFR-TKIs mentioned above.
Current research showing that approximately half of the drug resistance generated after EGFR-TKI treatment relates to the secondary mutation (T790M) at exon 20 of EGFR. In this regard, several irreversible inhibitors, such as Afatinib (BIBW-2992), Canertinib (CI-1033), Neratinib (HKI-272), CO-1686, HM781-36B and the like are developed; they can solve the drug resistance problem of the EGFR-TKIs indicated above. These drug molecules share a common structural feature, that is, the existence of an acrylamide functional group. This functional group can form covalent bond with cysteine 773 (Cys733) at the ATP binding region of EGFR. Such covalent binding can irreversibly block the self phosphorylation of EGFR, and effectively inhibit the signal transduction of cancer cells. Therefore these drugs show higher in vitro and in vivo anti-tumor activity.